ATBECHDEDKESFRGBGRITLILUNLSEMCPTIESILTLVFIROMKCYALTRBGCZEEHUPLSK..HRIS..MTNORS..SM..................*JBDM Ver 0.1.59 (03 Mar 2017) - 2100000/02948454EUROPEAN PATENT SPECIFICATIONB120170531EP14708337.2201401242015072420160825enenenDE0197201320130124IN20170531201722201512022015492017053120172220170215C07D 487/04 20060101AFI20140812BHEP A61K 31/53 20060101ALI20140812BHEP deTRIAZINVERBINDUNGEN UND VERFAHREN ZUR HERSTELLUNG DAVONenTRIAZINE COMPOUNDS AND A PROCESS FOR PREPARATION THEREOFfrCOMPOSÉS DE TRIAZINE ET PROCÉDÉ DE PRÉPARATION DE CEUX-CIWO-A1-00/71129WO-A1-2009/117157WO-A2-03/042172WO-A2-2006/004636US-A1- 2006 211 695US-A1- 2011 183 983US-A1- 2012 077 814US-B1- 6 982 265HUNT J T ET AL: "Discovery of the Pyrrolo[2,1-f][1,2,4]triazine Nucleus as a New Kinase Inhibitor Template", JOURNAL OF MEDICINAL CHEMISTRY, vol. 47, no. 16, 23 June 2004 (2004-06-23) , pages 4054-4059, XP002532756, AMERICAN CHEMICAL SOCIETY, US ISSN: 0022-2623, DOI: 10.1021/JM049892U [retrieved on 2004-06-23]DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 13 November 2012 (2012-11-13), XP002723097, retrieved from STN Database accession no. 1403767-05-4DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 10 January 2010 (2010-01-10), XP002723098, retrieved from STN Database accession no. 1201784-97-5PATIL S A ET AL: "Synthesis pf pyrrolo[2,1-f][1,2,4]triazine congeners of nucleic acid purines via the N-amination of 2-substituted pyrroles[1]", J. HETEROCYCLIC CHEM., vol. 31, July 1994 (1994-07), pages 781-786, XP002444699, cited in the applicationBORZILLERI R M ET AL: "Design, Synthesis, and Evaluation of Orally Active 4-(2,4-Difluoro-5-(methoxycarbamoyl)phenyl amino)-pyrrolo[2,1-f][1,2,4]triazines as Dual Vascular Endothelial Growth Factor Receptor-2 and Fibroblast Growth Factor Receptor-1 Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 48, 17 May 2005 (2005-05-17), pages 3991-4008, XP002377626, AMERICAN CHEMICAL SOCIETY, US ISSN: 0022-2623, DOI: 10.1021/JM0501275WROBLESKI S T ET AL: "Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38alpha MAP kinase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, no. 8, 15 April 2008 (2008-04-15) , pages 2739-2744, XP022606382, PERGAMON, AMSTERDAM, NL ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2008.02.067 [retrieved on 2008-03-04]KUMAR, PradeepNational Chemical Laboratory Dr. Homi Bhabha RoadPune 411008INHARBINDU, AnandNational Chemical Laboratory Dr. Homi Bhabha RoadPune 411008INSHARMA, BrijeshNational Chemical Laboratory Dr. Homi Bhabha RoadPune 411008INCouncil of Scientific & Industrial Research An Indian registered body incorporated under the Registration of Societies Act (Act XXI of 1860)101332867PC-EP-21077851Anusandhan Bhawan Rafi MargNew Delhi 110 001INAwapatent AB101563223P.O. Box 5117200 71 MalmöSEALATBEBGCHCYCZDEDKEEESFIFRGBGRHRHUIEISITLILTLULVMCMKMTNLNOPLPTRORSSESISKSMTRIN201400005620140124enWO201411517120140731201431 FIELD OF THE INVENTION

The present invention relates to a process for preparation of triazine compounds. Particularly, the present invention relates to preparation of triazine compounds which are useful for screening of kinases and other related targets. More particularly, the present invention relates to the process for the preparation of novel triazine compounds.

BACKGROUND OF THE INVENTION

In the past decade, researcher's efforts focused at the discovery of therapeutically useful inhibitors of protein kinases have been intensified. These efforts have resulted in the identification of a variety of templates which, depending upon the nature of attached substituents, provide selective inhibition both within and across different protein kinase families. One such effort led to the discovery of pyrrolo [2,1-f][1,2,4]triazine nucleus as a novel kinase inhibitor template which effectively mimics the well-known quinazoline kinase inhibitor scaffold, which has been serving a core template for a variety of ATP-competitive kinase inhibitors.

Thus, the current trend of research is now focused on novel analogs of pyrrolo [2,1-f][1,2,4]triazine so as to provide potent biochemical inhibitors of the tyrosine kinase activity. There is ample literature available on synthesis of novel pyrrolo [2,1-f]1,2,4]triazine molecules.

Aqua mediated one pot facile synthesis of novel thioxo-1,2,4-triazin-5(2h)-one and [1,2,4] triazino[5,6-a] indole derivatives and their biological activities is disclosed by Harshita Sachdeva et al. in J. Chil. Chem. Soc, 57, No 4 (2012), págs: 1348-1354.

WO/2013/177983 (Yang Chunhao et al.) discloses pyrrolo [2,1-f][1,2,4]triazine compounds and their use for treating phosphatidylinositol-3 kinase related diseases such as cancer. EP2289894 (Dyckman Alaric et al.) relates to cycloalkyl, heterocyclo and heteroaryl pyrrolotriazine aniline compounds useful for treating p38 kinase-associated conditions.

Synthesis and antiproliferative activity of [1,2,4]triazino[4,3-a]indoles is reported in anticancer research 24: 3775-3780 (2004) by Paola Barraja et al.

An article titled "Discovery of pyrrolo[2,1-f][1,2,4]triazine C6-ketones as potent, orally active p38α MAP kinase inhibitors" by Dyckman AJ, Li T, et al published in Bio. org Med ChemLett. 2011, Aug 1;21(15):4633-7 discloses preparation of Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α and explored functional group modifications at the C6 position and concludes that incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.

Another article titled "Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38 alpha MAP kinase inhibitors" by Wrobleski ST et al published in Bio. Org. Med. Chem. Lett. 2008 Apr 15;18(8):2739-44, reports a novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38 alpha MAP kinase inhibitors.

Yet another article titled "Synthesis of pyrrolo[2,1-f][1,2,4]triazine congeners of nucleic acid purines via the N-amination of 2-substituted pyrroles" by Shirish A. Patil et al published in J. O. Heterocyclic chemistry volume 31, issue 4, pages 781-786, describes synthesis of several new 4-mono- and 2,4-disubstituted pyrrolo[2,1-f][1,2,4]triazines.l-aminopyrrole-2-carbonitrile intermediates were obtained by N-amination of the corresponding pyrrole-2-carboxaldehyde followed by CHO→CN conversion with either hydroxylamine-O-sulfonic acid or O-mesitylenesulfonylhydroxylamine. Cyclization of the product thus obtained with a variety of amidine reagents or, after conversion of the product to its corresponding amide followed by base-catalyzed annulation completed the synthesis of the title products.

OBJECTS OF THE INVENTION

The main objective of the present invention is to provide a process for the preparation of novel triazine compounds.

Still another objective of the present invention is to provide a process for the preparation of triazine compounds which are useful for screening of kinases and other related targets.

SUMMARY OF THE INVENTION

Disclosed but not claimed are triazine compounds of Formula II,

The structural formula of the representative compounds of triazine compounds of Formula II are selected from the group consisting of: pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (37), 5,7-dimethylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (38), [1,2,4]triazino[1,6-a]indol-4(3H)-one (04), 7 -methoxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one (41), 7,8-dimethoxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one (42), 7-(benzyloxy)-[1,2,4]triazino[1,6-a]indol-4(3H)-one (43), 4-oxo-3,4-dihydro-[1,2,4]triazino[1,6-a]indole-7-carbonitrile (44), 7-fluoro-[1,2,4]triazino[1,6-a]indol-4(3H)-one (45), 7-chloro-[1,2,4]triazino[1,6-a]indol-4(3H)-one (46), 7-bromo-[1,2,4]triazino[1,6-a]indol-4(3H)-one (47), 7-indo-1,2,4]triazino[1,6-a]indol-4(3H)-one (48), 7-hydroxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one (49), 6-fluoro-[1,2,4]triazino[1,6-a]indol-4(3H)-one (50), 6-chloro-1,2,4]triazino[1,6-a]indol-4(3H)-one (51), 6-promo-[1,2,4]triazino[1,6-a]indol-4(3H)-one (52), 6-indo-[1,2,4]triazino[1,6-a]indol-4(3H)-one (53), 6-hydroxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one (54), 7-nitro-[1,2,4]triazino[1,6-a]indol-4(3H)-one (55), 5-(morpholinomethyl)-[1,2,4]triazino[1,6-a]indol-4(3H)-one (56), 5-(pyrrolidin-1-ylmethyl)-[1,2,4]triazino[1,6-a]indol-4(3H)-one (57), 7-amino-[1,2,4]triazino[1,6-a]indol-4(3H)-one (58), 7-ethynyl-[1,2,4]triazino[1,6-a]indol-4(3H)-one (59), 7-(but-1-yn-1-yl)-[1,2,4]triazino[1,6-a]indol-4(3H)-one (60), 7-(pent-1-yn-1-yl)-[1,2,4]triazino[1,6-a]indol-4(3H)-one (61), 7-(phenylethynyl)-1,2,4]triazino[1,6-a]indol-4(3H)-one (62), 7-azido-[1,2,4]triazino[1,6-a]indol-4(3H)-one (63), 7-fluropyrrolo-[2,1-f][1,2,4]triazin-4(3H)-one (64), 7-chloropyrrolo-[2,1-f][1,2,4]triazin-4(3H)-one (65), 7-bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (66), 7-iodopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (67), and 7-nitropyrrolo[2,1 f][1,2,4]triazin-4(3H)-one (68).

The described triazine compounds of Formula II are useful for screening kinases and other related targets.

In an embodiment of the present invention a process for the preparation of triazine compounds of Formula II, said process comprising the steps of:

  1. (a) stirring compounds of Formula I with sodium hypochlorite, Methyl tertiary-butyl ether (MTBE), methyltrioctylammonium chloride (aliquat-336), aqueous NaOH, ammonium chloride and aqueous NH4OH at a temperature ranging between 25 °C to 35 °C for a period ranging between 2-4 hrs to obtain N-aminated substituted 2-carboxylate;
    • wherein R1, R2, and R3, are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, -NOa, I, Cl, Br, F, and -CH2-R7, where R7 is 5 or 6 membered saturated heterocyclic ring, comprising at least one heteroatom selected from the group consisting of N, which is directly attached to carbon atom of -CH2; or
    • R1 and R2 together form substituted or unsubstituted aromatic ring as set forth below: wherein R4, R5, and R6 are individually selected from the group consisting of hydrogen, (C1-C6) alkyl, -NH2, halogen, -OH, -CN, -NO2, aryl, alkylaryl, (C1-C8) alkoxy, aryloxy, arylalkoxy, N3, and R-C=C, where R is selected from the group consisting of hydrogen, (C1-C6)alkyl, aryl, and alkylaryl
  2. (b) heating the N-aminated substituted 2-carboxylate compounds as obtained in step (a) with formamide and ammonium acetate at 130 °C to 140 °C for a period ranging between 10 to 12 hr under nitrogen atmosphere to obtain triazine compounds of Formula II.

In another embodiment of the present invention compounds of Formula I used in step (a) are selected from the group consisting of:

In another embodiment of the present invention N-aminated substituted 2-carboxylate as obtained in step (a) is either N-aminated pyrrole substituted 2-carboxylate or N-aminated indole substituted 2-carboxylate.

In another embodiment of the present invention yield of triazine compounds of Formula II is in the range of 75 to 85 %.

BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

DETAILED DESCRIPTION OF THE INVENTION

The instant application discloses triazine compounds and a short method to synthesize triazines nucleus, wherein the method comprises amination followed by Leuckart reaction conditions of pyrrole/indole-2-carboxylates of Formula I to obtain corresponding [1,2,4] triazine compounds of Formula II.

The instant invention thus provides short and efficient route for synthesis of various fused nitrogen ring system derivatives selected from a number of pyrrole and indole triazines. The synthesis of pyrrole triazinones and indole triazinones according to the invention has been accomplished in the instant invention using Leuckart reaction conditions.

The invention provides one pot method for synthesis of pyrrole/indole [1,2,4] triazine compounds of Formula II comprising steps of;

  1. (a) subjecting pyrrole/indole-2-carboxylate compounds of Formula I to amination in presence of chloramine to obtain desired N-aminated pyrrole/indole-2-carboxylate in high yields;
  2. (b) adding the N-aminated pyrrole/indole-2-carboxylate compound obtained from step (a) to formamide and ammonium acetate under Leuckart conditions to obtain pyrrole/indole [1,2,4] triazine compounds of Formula II.

N-Amination of various commercially available pyrrole-2-carboxylates and indole-2-carboxylates of Formula I is carried out using mono chloramine. N-amino pyrrole-2-carboxylate and N-amino-indole-2-carboxylates thus obtained were heated overnight at 140°C under nitrogen atmosphere in formamide and ammonium acetate to give various pyrrole and indole triazine compounds of Formula II. The instant invention is schematically represented below in scheme 1.

The proposed mechanism for cyclization using Leuckart condition according to the invention is shown below in scheme 2:

According to preferred aspect, N-aminated ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (6) is prepared by adding aqueous sodium hypochlorite at room temperature to a vigorously stirred mixture of ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate in Methyl tertiary-butyl ether (MTBE), ammonium chloride, methyltrioctylammonium chloride (Aliquat-336), aqueous NaOH and aqueous NH4OH. The resulting reaction mixture was stirred at room temperature for an additional 2-4 h at the end of which, the complete disappearance of starting material and formation of product is observed by capillary GC and HPLC. The upper product-rich organic layer was separated from the spent aqueous layer and washed with aqueous Na2S2O3. The organic layer is then dried over anhydrous Na2SO4 and evaporated in vacuo to produce N-aminated ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (6). The N-amination of indole-2-caroboxylate, pyrrole-2-carboxylate and their derivatives according to the invention has been achieved using chloramine, which is generated in the aqueous layer through oxidation of ammonia by NaOCl. At the same time, the substrate is deprotonated in the organic phase methyl tertiary-butyl ether (MTBE) with the addition of a small amount of methyltrioctylammonium chloride (Aliquat-336), which promptly reacts with the small portion of chloramines present in the organic layer, affording the desired N-NH2 derivative in high yields.

In another preferred aspect, the solution of N-aminated ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (6) in formamide is added to NH4OAc under stirring. The resulting mixture is stirred for 12-14 h at reflux temperature. The reaction mixture is poured into cold water and further diluted with ethyl acetate. The layers are separated and the aqueous layer is repeatedly extracted with ethyl acetate and the combined organic layers are dried over Na2SO4, filtered, and concentrated. The solvents are removed under reduced pressure to give the crude product mixture as colorless solid. Silica gel column chromatography of the crude product using petroleum ether/EtOAc (3:1) as eluent gave (38) as a colorless crystalline solid.

The 1H NMR spectrum of 1 clearly indicated broad singlet for -NH2 at δ 4.68. Derivatives of N-amino pyrrole-2-carboxylate and N-amino-indole-2-carboxylates were heated overnight at 140°C under nitrogen atmosphere in formamide and ammonium acetate to give cyclized pyrrole and indoletriazines.

In the present invention, various pyrroletriazinones and indoletriazinones have been accomplished using Leuckart reaction conditions from N-aminated precursors of pyrrole-2-carboxylate and N-amino-indole-2-carboxylates as depicted in table 1. <b>Table 1:</b> One-pot synthesis of [1,2,4]triazino[1,6-a]indol-4(3H)-one and [1,2,4]triazino[1,6-a]pyrrole-4(3H)-one compounds Entry No. N-Amination precursors Products Yields 1. 83% 2. 84% 3. 78% 4. 81% 5. 85% 6. 73% 7. 67% 8. --- 9. --- 12, X=CN 44, X=CN 13, X=F, 45, X=F, 14, X=Cl, 46, X=Cl, 15, X=Br, 47, X=Br, 16, X=I 48, X=I 17, X=OH 49, X=OH 10. -- 18, X=F 19, X=Cl 20, X=Br 50, X=F 21, X=I 51, X=Cl 22, X=OH 52, X=Br 53, X=I 54, X=OH 11. -- 12. -- 13. -- 14. -- 15. -- 27, R=H, 59, R=H, 28, R=Me 60, R=Me 29, R=Et 61, R=Et 30, R=Ph 62, R=Ph 16. -- 17. -- 64, X=F 32, X=F 65, X=Cl 33, X=Cl 66, X=Br 34, X=Br 67, X=I 35, X=I 68, X=NO2 36, X=NO2

The compounds of Formula II were synthesized according to invention encompasses triazine compounds as depicted in Table 2. <b>Table 2:</b> IUPAC names of the compounds synthesized S. No. Compound No. I.U.P.A.C Names i. 37 pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one ii. 38 5,7-dimethylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one iii. 39 6-nitropyrrolo[2,1-f|[1,2,4]triazin-4(3H)-one iv. 40 7-methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one v. 04 [1,2,4]triazino[1,6-a]indol-4(3H)-one vi. 41 7-methoxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one vii. 42 7,8-dimethoxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one viii. 43 7-(benzyloxy)-[1,2,4]triazino[1,6-a]indol-4(3H)-one ix. 44 4-oxo-3,4-dihydro-[1,2,4]triazino[1,6-a]indole-7-carbonitrile x. 45 7-fluoro-[1,2,4]triazino[1,6-a]indol-4(3H)-one xi. 46 7-chloro-[1,2,4]triazino[1,6-a]indol-4(3H)-one xii. 47 7-bromo-[1,2,4]triazino[1,6-a]indol-4(3H)-one xiii. 48 7-iodo-[1,2,4]triazino[1,6-a]indol-4(3H)-one xiv. 49 7-hydroxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one xv. 50 6-fluoro-[1,2,4]triazino[1,6-a]indol-4(3H)-one xvi. 51 6-chloro-[1,2,4]triazino[1,6-a]indol-4(3H)-one xvii. 52 6-bromo-[1,2,4]triazino[1,6-a]indol-4(3H)-one xviii. 53 6-iodo-[1,2,4]triazino[1,6-a]indol-4(3H)-one xix. 54 6-hydroxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one xx. 55 7-nitro-[1,2,4]triazino[1,6-a]indol-4(3H)-one xxi. 56 5-(morpholinomethyl)-[1,2,4]triazino[1,6-a]indol-4(3H)-one xxii. 57 5-(pyrrolidin-1-ylmethyl)-[1,2,4]triazino[1,6-a]indol-4(3H)-one xxiii. 58 7-amino-[1,2,4]triazino[1,6-a]indol-4(3H)-one xxiv. 59 7-ethynyl-[1,2,4]triazino[1,6-a]indol-4(3H)-one xxv. 60 7-(but-1-yn-1-yl)-[1,2,4]triazino[1,6-a]indol-4(3H)-one xxvi. 61 7-(pent-1-yn-1-yl)-[1,2,4]triazino[1,6-a]indol-4-(3H)-one xxvii. 62 7-(phenylethynyl)-[1,2,4]triazino[1,6-a]indol-4-(3H)-one xxviii. 63 7-azido-[1,2,4]triazino[1,6-a]indol-4(3H)-one xxix. 64 7-fluoropyrrolo[2,1-f][1,2,4]triazin-4(3H)-one xxx. 65 7-chloropyrrolo[2,1-f][1,2,4]triazin-4(3H)-one xxxi. 66 7-bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one xxxii. 67 7-iodopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one xxxiii. 68 7-nitropyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

The N-aminated precursors as well as cyclized triazines are characterized by spectral data. The1H NMR spectrum of compound 38 showed the presence of olefinic proton at δ 7.52 (s, 1H) and in 13C NMR spectrum of compound 38 showed the presence of amide carbonyl at 159.9 ppm. confirms the formation of [1,2,4]triazino[1,6-a]indol-4(3H)-one and [1,2,4]triazino[1,6-a]pyrrole-4(3H)-one. Further in order to confirm reaction product 38, recrystallisation was done by slow evaporation of the solution mixture of ethyl acetate and hexane to give the clear crystalline solid, which was analysed for single X-ray crystallography. The ORTEP diagram (Fig. 1) clearly established the formation of triazines.

Described, but not claimed, are triazine compounds of Formula II,

The triazine compounds of Formula II, are selected from the group consisting of: Compound No. I.U.P.A.C Names 38 5,7-dimethylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one 04 [1,2,4]triazino[1,6-a]indol-4(3H)-one 41 7-methoxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one 42 7,8-dimethoxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one 43 7-(benzyloxy)-[1,2,4]triazino[1,6-a]indol-4(3H)-one 44 4-oxo-3,4-dihydro-[1,2,4]triazino[1,6-a]indole-7-carbonitrile 45 7-fluoro-[1,2,4]triazino[1,6-a]indol-4(3H)-one 46 7-chloro-[1,2,4]triazino[1,6-a]indol-4(3H)-one 47 7-bromo-[1,2,4]triazino[1,6-a]indol-4(3H)-one 48 7-iodo-[1,2,4]triazino[1,6-a]indol-4(3H)-one 49 7-hydroxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one 50 6-fluoro-1,2,4]triazino[1,6-a]indol-4(3H)-one 51 6-chloro- 1,2,4]triazino[1,6-a]indol-4(3H)-one 52 6-bromo-1,2,4]triazino[1,6-a]indol-4(3H)-one 53 6-iodo-[1,2,4]triazino[1,6-a]indol-4(3H)-one 54 6-hydroxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one 55 7-nitro-[1,2,4]triazino[1,6-a]indol-4(3H)-one 56 5-(morpholinomethyl)-[1,2,4]triazino[1,6-a]indol-4(3H)-one 57 6-(pyrrolidine-1-ylmethyl)-[1,2,4]triazino[1,6-a]indol-4(3H)-one 58 7-amino-[1,2,4]triazino[1,6-a]indol-4(3-H)-one 59 7-ethynyl-[1,2,4]triazino[1,6-a]indol-4(3H)-one 60 7-(but-1-yn-1-yl)-[1,2,4]triazino[1,6-a]indol-4(3H)-one 61 7-(pent-1-yn-1-yl)-[1,2,4]triazino[1,6-a]indol-4(3H)-one 62 7-(phenylethynyl)-[1,2,4] triazino[1,6-a]indol-4(3H)-one 63 7-azido-[1,2,4]triazino[1,6-a]indol-4(3H)-one 64 7-fluoropyrrolo[2,1-f][1,2,4]triazin-4(3H)-one 65 7-chloropyrrolo[2,1-f][1,2,4]triazin-4(3H)-one 66 7-bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one 67 7-iodopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one 68 7-nitropyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

Also disclosed, but not claimed, is a pharmaceutical composition comprising instant triazine compounds of Formula II or its pharmaceutically acceptable salts, along with pharmaceutically acceptable excipients or carriers, for the treatment of cancer in human. Further the composition may be formulated into preparations such as solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, syrup, solutions, injections, gels and microspheres etc.

Generally, the quantity of active compound of Formula II ranges between 0.5% to 90% by weight of the composition. Normally, the effective amount of dosage of triazine compounds will be in the range of about 0.1 to about 100 mg/kg, more preferably about 1.0 mg to about 50 mg/kg of body weight/day.

The pharmaceutical compositions can be prepared by combining a compound of Formula II the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient. The excipients or carriers are selected from the group such as diluents, disintegrants, binders, lubricants, coatings layer, stabilizers, preservatives, glidants.

EXAMPLES

Following are the examples given to further illustrate the invention and should not be construed to limit the scope of the present invention.

Example 1 General Experimental Procedure for N-amination Reaction

Aqueous sodium hypochlorite (58.76 ml of ca. 9% solution) was added over a period of 20 min, at room temperature (25 °C), to a vigorously stirred mixture of (3,4,5,6-substitued-1-H-pyrrole/indole-2-carboxylic acid ethyl ester) (2 g, 8.9 mmol) in MTBE (24 ml), ammonium chloride (2.9 g, 53.2 mmol), methyltrioctylammonium chloride (Aliquat-336) (0.1 g), aqueous NaOH (25.6 ml of 28.4% solution) and aqueous NH4OH (8.28 ml of 28% solution). The resulting reaction mixture was stirred at room temperature for an additional 2-4 h at the end of which time the complete disappearance of starting material and formation of product was observed by capillary GC and HPLC. The upper product-rich organic layer was separated from the spent aqueous layer and washed with aqueous Na2S2O3 (40 ml). The organic layer was then dried over anhydrous Na2SO4 and evaporated in vacuo to produce 2.01 g of (1-amino-3,4,5,6-substitued-1-H-pyrrole/indole-2-carboxylic acid ethyl ester) (94% yield).

Example 2 General Experimental Procedure for Cyclization Reaction

To a stirring solution of (1-amino-3,4,5,6-substitued-1-H-pyrrole/indole-2-carboxylic acid ethyl ester) in formamide (5ml) was added NH4OAc. The resulting mixture was heated overnight at 140°C under nitrogen atmosphere. The mixture was poured into cold water and further diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The solvents were removed under reduced pressure to give the crude product mixture as colorless solid. Silica gel column chromatography of the crude product using petroleum ether/EtOAc (3:1) as eluent gave (Pyrrolo/Indole[1,2,4]triazin-4(3H)-one) (83% yield) as a colorless crystalline solid.

Using the above procedure, the following cyclized triazines compounds have been prepared.

Example 3 5,7-dimethylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (38)

Name of Compound Mol. Wt mmoles Equivalent Density Weight/volume ethyl 1-amino-3,5-dimethyl-1H-pyrrole-2-carboxylate 163.18 1.23 1 200mg NH4OAc 77.08 1.845 1.5 142.21mg Time & Temp 140°C & 12h

Example 4 pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (37)

Name of Compound Mol. Wt mmoles Equivalent Density Weight/volume ethyl 1-amino-1H-pyrrole-2-carboxylate 135.12 1.48 1 200mg NH4OAc 77.08 2.22 1.5 171.12mg Time & Temp 140°C & 12h

Example 5 7-methoxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one (41)

Name of Compound Mol. Wt mmoles Equivalent Density Weight/volume ethyl 1-amino-5-methoxy-1H-indole-2-carboxylate 215.07 0.93 1 200mg NH4OAc 77.08 1.4 1.5 107.53mg Time & Temp 140°C & 12h

Example 6 7,8-dimethoxy-[1,2,4]triazino[1,6-a]indol-4(3H)-one (42)

Name of Comp. Mol.Wt mmoles equivalent density Weight/volume ethyl 1-amino-5,6-dimethoxy-1H-indole-2-carboxylate 245.23 0.82 1 200mg NH4OAc 77.08 1.23 1.5 94.80mg Time & Temp 140°C & 12h

Example 7 6-nitropyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (39)

Name of Compound Mol. Wt mmoles Equivalent Density Weight/volume ethyl 1-amino-4-nitro-1H-pyrrole-2-carboxylate 180.12 1.11 1 200mg NH4OAc 77.08 1.67 1.5 128.34mg Time & Temp 140°C & 12h

Example 8 [1,2,4]triazino[1,6-a]indol-4(3H)-one (04)

Name of Compound Mol. Wt mmoles Equivalent Density Weight/volume ethyl 1-amino-1H-indole-2-carboxylate 185.18 1.08 1 200mg NH4OAc 77.08 1.62 1.5 124.87mg Time & Temp 140°C & 12h

ADVANTAGES OF INVENTION

The instant method is short and efficient for synthesis of various fused nitrogen ring system derivatives also the method avoids cumbersome intermediate steps and expensive solvents. Therefore, the instant invention is cost effective and industrially viable.

 A process for the preparation of triazine compound of Formula II, wherein, R1 is selected from the group consisting of hydrogen, -NO2, Br, F, and -CH2-R7, where R7 is 5 or 6 membered saturated heterocyclic ring, comprising at least one heteroatom selected from the group consisting of N, which is directly attached to carbon atom of -CH2; and wherein, R2 is selected from the group consisting of -NO2, I, Cl, F, and -CH2-R7, where R7 is 5 or 6 membered saturated heterocyclic ring, comprising at least one heteroatom selected from the group consisting of N which is directly attached to carbon atom of -CH2; and wherein, R3 is selected from the group consisting of hydrogen, -NO2, I, F, and -CH2-R7, where R7 is 5 or 6 membered saturated heterocyclic ring, comprising at least one heteroatom selected from the group consisting of N, which is directly attached to carbon atom of -CH2; or R1 and R2 together form substituted or unsubstituted aromatic ring as set forth below: wherein R4, R5, and R6 are individually selected from the group consisting of hydrogen, (C1-C6) alkyl, -NH2, halogen, -OH, -CN, -NO2, aryl, alkylaryl, (C1-C8) alkoxy, aryloxy, arylalkoxy, N3, and R-C≡C-, where R is selected from the group consisting of hydrogen, (C1-C6)alkyl, aryl, and alkylaryl,
said process comprising the steps of: (a) stirring compound of Formula I with sodium hypochlorite, Methyl tertiary-butyl ether (MTBE), methyltrioctylammonium chloride (aliquat-336), aqueous NaOH, ammonium chloride and aqueous NH4OH at a temperature ranging between 25 °C to 35 °C for a period ranging between 2- 4 hrs to obtain N-aminated substituted 2-carboxylate; (b) heating the N-aminated substituted 2-carboxylate compounds as obtained in step (a) with formamide and ammonium acetate at 130 °C to 140 °C for a period ranging between 10 to 12 hr under nitrogen atmosphere to obtain triazine compounds of Formula II. The process as claimed in claim 1, wherein the compound of Formula I is selected from the group consisting of: ethyl 1H-pyrrole-2-carboxylate (5), ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (6), ethyl 4-nitro-1H-pyrrole-2-carboxylate (7), ethyl 5-methyl-1H-pyrrole-2-carboxylate (8), ethyl 1H-indole-2-carboxylate (1), ethyl 5-methoxy-1H-indole-2-carboxylate (9), ethyl 5,6-dimethoxy-1H-indole-2-carboxylate (10), ethyl 5-(benzyloxy)-1H-indole-2-carboxylate (11), ethyl 5-cyano-1H-indole-2-carboxylate (12), ethyl 5-fluoro-1H-indole-2-carboxylate (13), ethyl 5-chloro-1H-indole-2-carboxylate (14), ethyl 5-bromo-1H-indole-2-carboxylate (15), ethyl 5-iodo-1H-indole-2-carboxylate (16), ethyl 5-hydroxy-1H-indole-2-carboxylate (17), ethyl 4-fluoro-1H-indole-2-carboxylate (18), ethyl 4-chloro-1H-indole-2-carboxylate (19), ethyl 4-bromo-1H-indole-2-carboxylate (20), ethyl 4-iodo-1H-indole-2-carboxylate (21), ethyl 4-hydroxy-1H-indole-2-carboxylate (22), ethyl 5-nitro-1H-indole-2-carboxylate (23), ethyl 3-(morpholinomethyl)-1H-indole-2-carboxylate (24), ethyl 3-(pyrrolidin-1-ylmethyl)-1H-indole-2-carboxylate (25), ethyl 5-amino-1H-indole-2-carboxylate (26), ethyl 5-ethynyl-1H-indole-2-carboxylate (27), ethyl 5-(prop-1-yn-1-yl)-1H-indole-2-carboxylate (28), ethyl 5-(but-1-yn-1-yl)-1H-indole-2-carboxylate (29), ethyl 5-(phenylethynyl)-1H-indole-2-carboxylate (30), ethyl 5-azido-1H-indole-2-carboxylate (31), ethyl 5-fluoro-1H-pyrrole-2-carboxylate (32), ethyl 5-chloro-1H-pyrrole-2-carboxylate (33), ethyl 5-bromo-1H-pyrrole-2-carboxylate (34), ethyl 5-iodo-1H-pyrrole-2-carboxylate (35), and ethyl 5-nitro-1H-pyrrole-2-carboxylate (36). The process as claimed in claim 1, wherein N-aminated substituted 2-carboxylate as obtained in step (a) is either N-aminated pyrrole substituted 2-carboxylate or N-aminated indole substituted 2-carboxylate. The process as claimed in claim 1, wherein yield of triazine compounds of Formula II is in the range of 75 to 85 %. Verfahren zur Herstellung einer Triazinverbindung der Formel II, worin R1 aus der Gruppe bestehend aus Wasserstoff, -NO2, Br, F und -CH2-R7 ausgewählt ist, wobei R7 für einen 5- oder 6-gliedrigen gesättigten heterocyclischen Ring mit mindestens einem Heteroatom aus der Gruppe bestehend aus N, der direkt an das Kohlenstoffatom von -CH2 gebunden ist, steht; und worin R2 aus der Gruppe bestehend aus -NO2, I, Cl, F und -CH2-R7 ausgewählt ist, wobei R7 für einen 5- oder 6-gliedrigen gesättigten heterocyclischen Ring mit mindestens einem Heteroatom aus der Gruppe bestehend aus N, der direkt an das Kohlenstoffatom von -CH2 gebunden ist, steht; und worin R3 aus der Gruppe bestehend aus Wasserstoff, -NO2, I, F und -CH2-R7 ausgewählt ist, wobei R7 für einen 5- oder 6-gliedrigen gesättigten heterocyclischen Ring mit mindestens einem Heteroatom aus der Gruppe bestehend aus N, der direkt an das Kohlenstoffatom von -CH2 gebunden ist, steht; oder R1 und R2 zusammen einen substituierten oder unsubstituierten aromatischen Ring gemäß nachstehender Darstellung bilden: worin R4, R5 und R6 jeweils aus der Gruppe bestehend aus Wasserstoff, (C1-C6)-Alkyl, -NH2, Halogen, -OH, -CN, -NO2, Aryl, Alkylaryl, (C1-C8)-Alkoxy, Aryloxy, Arylalkoxy, N3 und R-C=C-ausgewählt sind, wobei R aus der Gruppe bestehend aus Wasserstoff, (C1-C6)-Alkyl, Aryl und Alkylaryl ausgewählt ist,
wobei das Verfahren folgende Schritte umfasst: (a) Rühren einer Verbindung der Formel I mit Natriumhypochlorit, Methyl-tert-butylether (MTBE), Methyltrioctylammoniumchlorid (Aliquat-336), wässrigem NaOH, Ammoniumchlorid und wässrigem NH4OH bei einer Temperatur im Bereich zwischen 25°C bis 35°C über einen Zeitraum im Bereich zwischen 2-4 h zum Erhalt eines N-aminierten substituierten 2-Carbonsäureesters; (b) Erhitzen der wie in Schritt (a) erhaltenen N-aminierten substituierten 2-Carbonsäureesterverbindungen mit Formamid und Ammoniumacetat auf 130°C bis 140°C über einen Zeitraum im Bereich zwischen 10 bis 12 h unter Stickstoffatmosphäre zum Erhalt von Triazinverbindungen der Formel II. Verfahren nach Anspruch 1, bei dem die Verbindung der Formel I aus der Gruppe bestehend aus: 1H-Pyrrol-2-carbonsäureethylester (5), 3,5-Dimethyl-1H-pyrrol-2-carbonsäureethylester (6), 4-Nitro-1H-pyrrol-2-carbonsäureethylester (7), 5-Methyl-1H-pyrrol-2-carbonsäureethylester (8), 1H-Indol-2-carbonsäureethylester (1), 5-Methoxy-1H-indol-2-carbonsäureethylester (9), 5,6-Dimethoxy-1H-indol-2-carbonsäureethylester (10), 5-(Benzyloxy)-1H-indol-2-carbonsäureethylester (11), 5-Cyano-1H-indol-2-carbonsäureethylester (12), 5-Fluor-1H-indol-2-carbonsäureethylester (13), 5-Chlor-1H-indol-2-carbonsäureethylester (14), 5-Brom-1H-indol-2-carbonsäureethylester (15), 5-Iod-1H-indol-2-carbonsäureethylester (16), 5-Hydroxy-1H-indol-2-carbonsäureethylester (17), 4-Fluor-1H-indol-2-carbonsäureethylester (18), 4-Chlor-1H-indol-2-carbonsäureethylester (19), 4-Brom-1H-indol-2-carbonsäureethylester (20), 4-Iod-1H-indol-2-carbonsäureethylester (21), 4-Hydroxy-1H-indol-2-carbonsäureethylester (22), 5-Nitro-1H-indol-2-carbonsäureethylester (23), 3-(Morpholinomethyl)-1H-indol-2-carbonsäureethylester (24), 3-(Pyrrolidin-1-ylmethyl)-1H-indol-2-carbonsäureethylester (25), 5-Amino-1H-indol-2-carbonsäureethylester (26), 5-Ethinyl-1H-indol-2-carbonsäureethylester (27), 5-(Prop-1-in-1-yl)-1H-indol-2-carbonsäureethylester (28), 5-(But-1-in-1-yl)-1H-indol-2-carbonsäureethylester (29), 5-(Phenylethinyl)-1H-indol-2-carbonsäureethylester (30), 5-Azido-1H-indol-2-carbonsäureethylester (31), 5-Fluor-1H-pyrrol-2-carbonsäureethylester (32), 5-Chlor-1H-pyrrol-2-carbonsäureethylester (33), 5-Brom-1H-pyrrol-2-carbonsäureethylester (34), 5-Iod-1H-pyrrol-2-carbonsäureethylester (35) und 5-Nitro-1H-pyrrol-2-carbonsäureethylester (36) ausgewählt wird. Verfahren nach Anspruch 1, bei dem es sich bei dem wie in Schritt (a) erhaltenen N-aminierten substituierten 2-Carbonsäureester entweder um N-aminierten substituierten Pyrrol-2-carbonsäureester oder um N-aminierten substituierten Indol-2-carbonsäureester handelt. Verfahren nach Anspruch 1, bei dem die Ausbeute an Triazinverbindungen der Formel II im Bereich von 75 bis 85% liegt. Procédé de préparation de composé de triazine de formule II, dans lequel, R1 est choisi dans le groupe constitué d'hydrogène, -NO2, Br, F, et -CH2-R7, où R7 est un cycle hétérocyclique saturé de 5 ou 6 chaînons, comprenant au moins un hétéroatome choisi dans le groupe constitué de N, qui est directement lié à l'atome de carbone de -CH2 ; et dans lequel, R2 est choisi dans le groupe constitué de -NO2, I, Cl, F et -CH2-R7, où R7 est un cycle hétérocyclique saturé de 5 ou 6 chaînons, comprenant au moins un hétéroatome choisi dans le groupe constitué de N, qui est directement lié à l'atome de carbone de -CH2 ; et dans lequel, R3 est choisi dans le groupe constitué d'hydrogène, -NO2, I, F, et -CH2-R7, où R7 est un cycle hétérocyclique saturé de 5 ou 6 chaînons, comprenant au moins un hétéroatome choisi dans le groupe constitué de N, qui est directement lié à l'atome de carbone de -CH2 ; ou R1 et R2 forment conjointement un cycle aromatique substitué ou non substitué comme décrit ci-dessous : dans lequel R4, R5, et R6 sont individuellement choisis dans le groupe constitué d'hydrogène, alkyle en C1-C6, -NH2, halogène, -OH, -CN, -NO2, aryle, alkylaryle, alcoxy en C1-C8, aryloxy, arylalcoxy, N3, et R-C≡C-, où R est choisi dans le groupe constitué d'hydrogène, alkyle en C1-C6, aryle et alkylaryle, ledit procédé comprenant les étapes de : (a) agitation du composé de formule I avec de l'hypochlorite de sodium, de l'éther méthyl-tert-butylique (MTBE), du chlorure de méthyltrioctylammonium (Aliquat 336), du NaOH aqueux, du chlorure d'ammonium et du NH4OH aqueux à une température dans la plage comprise entre 25 °C et 35 °C pendant une durée dans la plage comprise entre 2 et 4 h pour obtenir un 2-carboxylate substitué N-aminé ; (b) chauffage des composés de 2-carboxylate substitué N-aminé obtenus dans l'étape (a) avec du formamide et de l'acétate d'ammonium à 130 °C à 140 °C pendant une durée dans la plage comprise entre 10 et 12 h sous atmosphère d'azote pour obtenir des composés de triazine de formule II. Procédé selon la revendication 1, dans lequel le composé de formule I est choisi dans le groupe constitué des : 1H-pyrrole-2-carboxylate d'éthyle (5), 3,5-diméthyl-1H-pyrrole-2-carboxylate d'éthyle (6), 4-nitro-1H-pyrrole-2-carboxylate d'éthyle (7), 5-méthyl-1H-pyrrole-2-carboxylate d'éthyle (8), 1H-indole-2-carboxylate d'éthyle (1), 5-méthoxy-1H-indole-2-carboxylate d'éthyle (9), 5,6-diméthoxy-1H-indole-2-carboxylate d'éthyle (10), 5-(benzyloxy)-1H-indole-2-carboxylate d'éthyle (11), 5-cyano-1H-indole-2-carboxylate d'éthyle (12), 5-fluoro-1H-indole-2-carboxylate d'éthyle (13), 5-chloro-1H-indole-2-carboxylate d'éthyle (14), 5-bromo-1H-indole-2-carboxylate d'éthyle (15), 5-iodo-1H-indole-2-carboxylate d'éthyle (16), 5-hydroxy-1H-indole-2-carboxylate d'éthyle (17), 4-fluoro-1H-indole-2-carboxylate d'éthyle (18), 4-chloro-1H-indole-2-carboxylate d'éthyle (19), 4-bromo-1H-indole-2-carboxylate d'éthyle (20), 4-iodo-1H-indole-2-carboxylate d'éthyle (21), 4-hydroxy-1H-indole-2-carboxylate d'éthyle (22), 5-nitro-1H-indole-2-carboxylate d'éthyle (23), 3-(morpholinométhyl)-1H-indole-2-carboxylate d'éthyle (24), 3-(pyrrolidin-1-ylméthyl)-1H-indole-2-carboxylate d'éthyle (25), 5-amino-1H-indole-2-carboxylate d'éthyle (26), 5-éthynyl-1H-indole-2-carboxylate d'éthyle (27), 5-(prop-1-yn-1-yl)-1H-indole-2-carboxylate d'éthyle (28), 5-(but-1-yn-1-yl)-1H-indole-2-carboxylate d'éthyle (29), 5-(phényléthynyl)-1H-indole-2-carboxylate d'éthyle (30), 5-azido-1H-indole-2-carboxylate d'éthyle (31), 5-fluoro-1H-pyrrole-2-carboxylate d'éthyle (32), 5-chloro-1H-pyrrole-2-carboxylate d'éthyle (33), 5-bromo-1H-pyrrole-2-carboxylate d'éthyle (34), 5-iodo-1H-pyrrole-2-carboxylate d'éthyle (35), et 5-nitro-1H-pyrrole-2-carboxylate d'éthyle (36). Procédé selon la revendication 1, dans lequel le 2-carboxylate substitué N-aminé obtenu dans l'étape (a) est un 2-carboxylate substitué par pyrrole N-aminé ou un 2-carboxylate substitué par indole N-aminé. Procédé selon la revendication 1, dans lequel le rendement en composés de triazine de formule II est dans la plage de 75 à 85 %.
REFERENCES CITED IN THE DESCRIPTION

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Patent documents cited in the description

Non-patent literature cited in the description